Regression of Pathologic Changes Induced by the Long-term Administration of Contraceptive Steroids to Rodents

Abstract

The induction of pathologic changes with hormone steroids has been studied in rodents, although comprehensive studies are lacking on the potential reversibility of these lesions. For these purposes, groups of rats were treated with quingestanol acetate and quinestrol, a progestogen-estrogen combination, for 50 weeks and observed for a subsequent 30-week period. Treatment resulted in a significant body weight gain suppression and reduction of food consumption which recovered after withdrawal. Other significant treatment-related effects were hair loss, ataxia due to pituitary enlargement, mammary chain masses with histologic adenocarcinoma, lens opacities, ovarian atrophy with follicular arrest, and uterine atrophic changes with suppurative inflammation throughout 50 weeks. Cessation of treatment did not effect hair loss or lens opacities, while mammary chain masses decreased in size and in incidence; mammary gland tumors showed regressive changes including the disappearance of adenocarcinoma, and the incidence of ataxia diminished together with reduced pituitary weights. Chromophobe cell hyperplasia with decreased eosinophils and acidophils and hemorrhage into the pituitary was observed up to 50 weeks and the tinctorial affinity of basophils and acidophils returned after withdrawal. Ovaries and uteri, which become atrophic and sustained chronic suppurative inflammation in the treatment phase, showed reduction of inflammatory reaction and disappearance of suppuration after withdrawal, and endometrial regeneration occurred with luteal cells seen in the ovaries. These results revealed the regressive characteristics of some of the mammary gland carcinomas as well as steroid-induced endocrine and pathologic lesions other than tegumentary and ocular changes in rats receiving high levels of steroids for prolonged periods of time.

References

1. Balazs T , Ohtake S , and Noble JF (1969). Changes in the lenses of aging rats. Toxicol. Appl. Pharmacol. 14: 634.

2. Blaquier JA (1964). Effects of prolonged oral administration of progestational steroids in the female rat. Acta Physiol. Lat. Am. 14:255–263.

3. Bühler H , Pirovino M , Akovbiantz A , Altorfer J , Weitzel M , Maranta E , and Schmid M (1982). Regression of liver cell adenoma. A follow-up study of three consecutive patients after discontinuation of oral contraceptive use. Gastroenterology 82:775–782.

4. Cutts JH (1964). Estrogen-induced breast cancer in the rat. Proc. Can. Cancer Res. Conf. 6:50–68.

5. Cutts JH (1964). Estrone-induced mammary tumors in the rat. II. Effect of alterations in the hormonal environment on tumor induction, behavior, and growth. Cancer Res. 24:1124–1130.

6. Cutts JH and Froude GC (1968). Regression of estrone-induced mammary tumors in the rat. Cancer Res. 28:2413–2418.

7. Dao TL (1964). Carcinogenesis of mammary gland in rat. Prog. Exp. Tumor Res. 5:157–216.

8. Dao TL (1969). Studies on mechanism of carcinogenesis in the mammary gland. Prog. Exp. Tumor Res. 11:235–261.

9. El-Etreby MF (1980). Influences of contraceptive steroids on tumor development in experimental animals and man: a short review. In: Pharmacological Modulation of Steroid Action, E Genazzani , F DiCarlo , and WIP Mainwaring , (eds). Raven Press, New York, pp. 239–260.

10.

10. Ercoli A , Bruni G , Falconi G , Gardi R , and Meli A (1960). Biological activities of some steroid ethers: methyltestosterone enol ethers. Endocrinology 67:521–525.

11.

11. Ercoli A and Gardi R (1960). Δ4-3-Keto steroidal enol ethers; paradoxical dependency of their effectiveness on the administration route. J. Am. Chem. Soc. 82:746–748.

12.

12. Ercoli A and Gardi R (1961). Cyclopentyl ethers of oestrogenic steroids. Chem. Ind. (Lond.) 1037–1038.

13.

13. Ercoli A , Gardi R , and Bruni G (1964). Ether derivatives of steroid hormones. Res. Prog. Org. Biol. Med. Chem. 1:155–207.

14.

14. Ercoli A , Pellegrini R , and Falconi G (1961). Cyclopentyl ethers of estrogenic phenols; biological study and clinical activity. In: Proceedings of the Third World Congress on Gynecology and Obstetrics, Vienna, Abstract 173, p. 4.

15.

15. Fitzgerald J , Goldenthal E , and de la Iglesia FA (1982). Ten-year oral toxicity study with Norlestrin in Rhesus Monkeys. J. Toxicol. Environ. Health 10:879–896.

16.

16. Giannina T , Steinetz BG , and Meli A (1967). General biology of quinestrol. Int. J. Fertil. 12:142–147.

17.

17. Giannina T , Steinetz BG , Rassaert CL , McDougall EA , and Meli A (1969). Biological profile of quingestanol acetate. Proc. Soc. Exp. Biol. Med. 131:781–789.

18.

18. Holmes RL and Mandl AM (1962). The effect of norethynodrel on the ovaries and the pituitary gland of adult female rats. J. Endocrinol. 24:497–515.

19.

19. Husain SM and Pincus G (1968). Effects of oral administration of a norethynodrel-mestranol combination (Enovid) in rats. Rev. Can. Biol. 27:217–224.

20.

20. Lumb G and de la Iglesia FA (1970). Electron microscopic studies of the pituitary after estrogen administration. Am. J. Pathol. 58: 36–37a.

21.

21. Machnik G , Chemnitius K-H , Niekrenz H (1983). Liver neoplasms after long-term application in rats. Exp. Pathol. 24:183–187.

22.

22. Meli A (1963). Route of administration as a factor influencing the biological activity of certain androgens and their corresponding 3-cyclopentyl enol ethers. Endocrinology 72:715–719.

23.

23. Meli A , Honrath WL , and Wolff A (1964). Mechanism by which 3-enol etherification enhances the oral activity of methyltestosterone in rats. Endocrinology 74:79–82.

24.

24. Meli A and Steinetz BG (1966). Influence of etherification or 3-enol etherification on the biology and metabolism of steroids. Trans. N. Y. Acad. Sci. 28:623–627.

25.

25. Meli A , Steinetz BG , Beach VL , Wolff A , and Giannina T (1965). Biological and chromatographic evidence for the storage of ethinyl estradiol-3-cyclopentyl ether in rat brain. Proc. Soc. Exp. Biol. Med. 119:602–606.

26.

26. Meli A , Wolff A , Honrath WL (1963). The mechanism by which 3-etherification with cyclopentyl alcohol enhances the oral activity of ethinyl estradiol. Steroids 2:417–424.

27.

27. Paget GE and Eccleston E (1960). Simultaneous specific demonstration of thyrotroph, gonadotroph and acidophil cells in the anterior hypophysis. Stain Technol. 35:119–122.

28.

28. Philipson B (1969). Biophysical studies on normal and cataractous rat lenses. Acta Ophthalmol. (Suppl. Copenh.) 47: 1–30.

29.

29. Ray DE and Seerley RW (1966). Oestrus and ovarian morphology in gilts following treatment with orally effective steroids. Nature 211:1102–1103.

30.

30. Ray JA and Schut L (1969). Cataracts and other lesions in rats receiving a synthetic progestin-estrogen. Toxicol. Appl. Pharmacol. 14:634–635.

31.

31. Saunders FJ (1964). Effects of steroids on pituitary gonadotropin and fertility. Recent Prog. Horm. Res. 20:395–426.

32.

32. Saunders FJ and Drill VA (1958). Some biological activities of 17-ethinyl and 17-alkyl derivatives of 17-hydroxyesterones. Ann. N. Y. Acad. Sci. 71:516–531.

33.

33. Schardein JL (1980). Studies of the components of an oral contraceptive agent in albino rats. I. Estrogenic component. J. Toxicol. Environ. Health 6:885–894.

34.

34. Schardein JL (1980). Studies of the components of an oral contraceptive agent in albino rats. II. Progestogenic component and comparison of effects of the components and the combined agent. J. Toxicol. Environ. Health 6:895–906.

35.

35. Schardein JL , Kaump DH , Woosley ET , and Jellema MM (1970). Long-term toxicologic and tumorigenesis studies on an oral contraceptive agent in albino rats. Toxicol. Appl. Pharmacol. 16:10–23.

36.

36. Vaughn TC , Haney AF , Wiebe RH , Kramer RS , and Hammond CB (1980). Spontaneous regression of prolactin-producing pituitary adenomas. Am. J. Obstet. Gynecol. 136:980–982.

37.

37. Wanless IR , Medline A (1982). Role of estrogens as promoters of hepatic neoplasia. Lab. Invest. 46:313–320.

38.

38. Yager JD Jr , and Yager R (1980). Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague-Dawley rats. Cancer Res. 40:3680–3685.